Targeting the Gut Microbiome in Renal and Other GU Cancers
– Excellent overview of ongoing investigations into novel approaches
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The gut microbiome has become an emerging focus of cancer research in recent years. Preclinical and early-phase clinical studies have demonstrated its role not just in carcinogenesis, but also in anti-tumor response to systemic therapy, development of resistance, and correlation with treatment-related toxicities. In a review in the , Drs. Nguyen and Vaishampayan review the clinical applications of gut microbiome in genitourinary (GU) cancers.
Probiotics are "live microorganisms which, when consumed in adequate amounts, confer beneficial health effects on the host" by the food and agricultural organization. Probiotics are considered genetically safe, are nonpathogenic, and possess immunomodulatory properties.
On the other hand, are substrates that are selectively utilized by host microorganisms conferring a health benefit. Systemic chemotherapy often results in , altering the composition of the gut microbiome.
Probiotics have been previously used in oncology patients to , inflammation, and performance status. In GU cancers, microbiome research has been a focal area of interest, particularly since the advent of immune checkpoint inhibitors (ICIs). Nguyen and Vaishampayan describe the current state and future directions of microbiome modulation in the treatment of renal cell, urothelial, and prostate cancer with a focus on immunotherapy.
Gut microbiome dysbiosis may result in decreased T cell infiltration signaling and cytotoxic activity. Microbiome profiling at the time of screening biopsies -- evaluated by rectal swab or gut composition analysis -- has revealed a notable distinction between patients found to have prostate cancer compared with benign prostatic conditions.
Similarly, urinary microbiome analysis reveals greater abundance of Acinetobacter, Anaerococcus, and Sphingobacterium species in patients with urothelial cancer. Interventions including probiotic supplementation, dietary modifications, and fecal microbiota transplantation (FMT) are being actively evaluated to improve outcomes with ICI treatment in GU cancers.
In a randomized phase I study, evaluated the effect of live bacterial supplementation with CBM588 in patients with metastatic renal cell carcinoma (mRCC). Patients randomized to CBM588 in addition to standard-of-care cabozantinib/nivolumab demonstrated higher objective response rates compared with cabozantinib/nivolumab alone (74% vs 20%, P=0.01). CBM588 also led to improvement in progression-free survival at 6 months (84% vs 60%) in this hypothesis-generating study. Similar studies in urothelial cancer are currently ongoing.
FMT is an emerging strategy for gut microbiome modulation, with trials underway in mRCC, evaluating the role of fecal transplant from ICI responders to non-responders as a mechanism of overcoming resistance. The role of FMT in combination with ICIs upfront is also being evaluated, with the goal being enhanced response and delay in development of resistance.
Another strategy under investigation is the use of FMT in reducing the risk of toxicities from ICIs as well as antiangiogenics. These and other promising trials are well summarized in this article.
Overall, the authors provide an excellent overview of preclinical and clinical data supporting ongoing investigation into novel approaches targeting the gut microbiome in GU cancers.
, is a GU medical oncologist at the University of Massachusetts Memorial Medical Center in Worcester.
Read the review here and an interview about it here.
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ASCO Educational Book
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